Conformational Analysis by NMR and Distance-Geometry Techniques of Deltorphin Analogs

To identify the peptide conformation that is preferentially recognized by the receptor, we have synthetized by solid-phase method a series of deltorphin I analogs with increasing selectivity for δ- and μ-opioid receptor. Structure-selectivity relationship of these peptides were evaluated on the basis of receptor-binding properties and conformational features, computed by two-dimensional NMR spectra and distance-geometry techniques. These compounds in solution are present with a large number of conformers with no defined secondary structural elements. The analysis of the average properties of these compounds indicate the presence of some distinct conformational preferences that can be related to the observed opioid receptor selectivities. Selectivity for the δ- and μ-opioid receptors can be ascribed to the spatial arrangement of the aromatic moieties. In addition, substitutions in position 2 and 4 are important for the correct arrangement and must be taken into account in the design of δ-opioid receptor-selective ligands.